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?-Arrestins regulate human cardiac fibroblast transformation and collagen
synthesis in adverse ventricular remodeling
#MMPMID25134464
Li J
; Philip JL
; Xu X
; Theccanat T
; Abdur Razzaque M
; Akhter SA
J Mol Cell Cardiol
2014[Nov]; 76
(?): 73-83
PMID25134464
show ga
Cardiac fibroblasts (CFs) produce and degrade the myocardial extracellular matrix
and are critical in maladaptive ventricular remodeling that can result in heart
failure (HF). ?-Arrestins are important signaling molecules involved in
?-adrenergic receptor (?-AR) desensitization and can also mediate signaling in a
G protein-independent fashion. We hypothesize that ?-arrestins play an important
role in the regulation of adult human CF biology with regard to myofibroblast
transformation, increased collagen synthesis, and myocardial fibrosis which are
important in the development of HF. ?-Arrestin1 & 2 expression is significantly
upregulated in adult human CF isolated from failing left ventricles and ?-AR
signaling is uncoupled with loss of ?-agonist-mediated inhibition of collagen
synthesis versus normal control CF. Knockdown of either ?-arrestin1 or 2 restored
?-AR signaling and ?-agonist mediated inhibition of collagen synthesis.
Overexpression of ?-arrestins in normal CF led to a failing phenotype with
increased baseline collagen synthesis, impaired ?-AR signaling, and loss of
?-agonist-mediated inhibition of collagen synthesis. ?-Arrestin knockdown in
failing CF diminished TGF-? stimulated collagen synthesis and also inhibited ERK
phosphorylation. Overexpression of ?-arrestins in normal CF increased basal
ERK1/2 and Smad2/3 phosphorylation and enhanced TGF-?-stimulated collagen
synthesis. This was prevented by pre-treatment with a MEK1/2 inhibitor. Enhanced
?-arrestin signaling appears to be deleterious in CF by promoting a pro-fibrotic
phenotype via uncoupling of ?-AR signaling as well as potentiating ERK and Smad
signaling. Targeted inhibition of ?-arrestins in CF may represent a therapeutic
strategy to prevent maladaptive myocardial fibrosis.
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